1. Field of the Invention
The present invention provides novel mitomycin analogs containing a disulfide group (Class 260, Subclass 326.24) and processes for the preparation thereof. These compounds are mitomycin A analogs in which the 7-alkoxy group bears an organic substituent incorporating a disulfide group. The present invention also provides a method of producing mitomycin A and derivatives thereof (Class 260, Subclass 326.24). Mitomycin A is an antibiotic of established utility, and the 7-O-substituted mitosane analogs thereof have similar utility.
Nomenclature--The systematic Chemical Abstracts name for mitomycin A based on the recent revision [Shirhata et al., J. Am. Chem. Soc., 105, 7199 (1983)] is:
[1aS-(1a.beta.,8.beta.,8a.alpha.,8b.beta.)]-8-[((aminocarbonyl)oxy)methyl]- 6,8a-dimethoxy-1,1a,2,8,8a,8b-hexahydro-5-methyarizino[2',3',3,4,]pyrrolo[1 ,2-a]indole-4,7-dione according to which the azirinopyrroloindole ring system is numbered as follows: ##STR1## PA0 1-(n-butyl)-3-(4-methylphenyl)triazene; PA0 1-(1-methylethyl)-3-(4-methylphenyl)triazene; PA0 1-(4-methylphenyl)-3-[2-(4-morpholinyl)ethyl]triazene; PA0 1-(4-methylphenyl)-3-[2-(2-pyridyl)ethyl]triazene; PA0 1-(2-benzylthiolethyl)-3-(4-methylphenyl)triazene; PA0 1-(4-chlorophenyl)-3-(2-methoxyethyl)triazene; PA0 1-(4-chlorophenyl)-3-(1,3-dioxol-2-ylmethyl)triazene; PA0 1-(4-chlorophenyl)-3-(tetrahydrofuran-2-ylmethyl)triazene. PA0 1-(n-butyl)-3-(.alpha.-napthyl)triazene PA0 1-(n-hexyl)-3-phenyltriazene PA0 1-ethyl-3-(2,4-dimethylphenyl)triazene PA0 1-(1-methylethyl)-3-(4-methoxyphenyl)triazene PA0 2-aminoethyl n-butyl disulfide; PA0 2-aminoethyl n-hexyl disulfide; PA0 2-aminoethyl n-octyl disulfide; PA0 2-aminoethyl n-decyl disulfide; PA0 2-aminoethyl phenyl disulfide; PA0 2-aminoethyl benzyl disulfide. PA0 1-[2-(2-acetamidoethyldithiol)ethyl]-3-(4-methylphenyl)triazene; PA0 1-[2-(3-nitro-2-pyridyldithio)ethyl]-3-(4-methylphenyl)triazene. PA0 1-[2-(3-nitro-2-pyridyldithio)ethyl]-3-(4-chlorophenyl)triazene; PA0 1-[2-(3-nitro-2-pyridyldithio)propyl]-3-(4-methylphenyl)triazene; PA0 1-[2-(2-pyridyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -[2-(phenyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -[2-(butyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -[2-(4-methoxyphenyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -[2-(4-nitrophenyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -{2-[(2-benzoylaminoethyl)dithio]ethyl}-3-(4-methylphenyl)triazene; PA0 1 -[2-(4-chloro-2-naphthyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -[2-(cyclopropylmethyldithio)ethyl]-3-(4-methylphenyl)triazene; PA0 1 -{2-[(2-phenoxyethyl)dithio]ethyl}-3-(4-methylphenyl)triazene.
A trivial system of nomenclature which has found wide use in the mitomycin literature identifies the foregoing ring system including several of the characteristic substituents of the mitomycins as mitosane. ##STR2## According to this system, mitomycin A is 7,9a-dimethoxymitosane itomycin C is 7-amino-9a-methoxymitosane. As to the stereochemical configuration of the products of this invention, it is intended when identifying them by the root name "mitosane" or by structural formula to identify the stereochemical configuration thereof as the same as that of mitomycin A or C. ##STR3##
2. Disclosure Statement
Mitomycin C is an antibiotic which is produced by fermentation and is presently on sale under Food and Drug Administration approval in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed (Mutamycin.RTM. Bristol Laboratories, Syracuse, New York 13221, Physicians' Desk Reference 37th Edition, 1983, pp. 747 and 748). Mitomycin C and its production by fermentation is the subject of U.S. Pat. 3,660,578 patented May 2, 1972 claiming priority from earlier applications including an application filed in Japan on April 6, 1957.
The structures of mitomycins A, B, C, and of porfiromycin were first published by J. S. Webb et al. of Lederle Laboratories Division American Cyanamid Company, J. Am. Chem. Soc., 84, 3185-3187 (1962). One of the chemical transformations used in this structure study to relate mitomycin A and mitomycin C was the conversion of the former, 7,9a-dimethoxymitosane, by reaction with ammonia to the latter, 7-amino-9a-methoxymitosane. Displacement of the 7-methoxy group of mitomycin A has proven to be a reaction of considerable interest in the preparation of antitumor active derivatives of mitomycin C. Recently the stereochemical configurations of positions 1, 1a, 8a and 8b have been shown to be as indicated above with respect to the Chemical Abstracts nomenclature [Shirhata et al., J. Am. Chem Soc., 105, 7199-7200 (1983)]. The earlier literature refers to the enantiomer.
The following articles and patents deal inter alia with the conversion of mitomycin A to a 7-substituted amino mitomycin C derivative having antitumor activity. The object of this research was to prepare derivatives which were more active, and particularly which were less toxic than mitomycin C: Matsui et al., J. Antibiotics, XXI, 189-198 (1968); Konishita et al., J. Med. Chem., 14, 103-109 (1971); Iyengar et al., J. Med. Chem., 24, 975-981 (1981);
Iyengar, Sami, Remers and Bradner, Abstracts of Papers, 183rd Annual Meeting of the American Chemical Society, Las Vegas, Nev., March 1982, Abstract No. MEDI 72;
Cosulich et al., U.S. Pat. No. 3,332,944, issued July 25, 1967;
Matsui et al., U.S. Pat. No. 3,420,846, issued Jan. 7, 1969;
Matsui et al., U.S. Pat. No. 3,450,705, issued June 17, 1969;
Matsui et al., U.S. Pat. No. 3,514,452, issued May 26, 1970;
Nakano et al., U.S. Pat. No. 4,231,936, issued Nov. 4, 1980;
Remers, U.S. Pat. No. 4,268,676, issued May 19, 1981.
The following patent applications deal with the preparation of 7-substituted amino mitomycin C derivatives in which the substituent incorporates a disulfide linkage.
Kono et al., European Patent Application No. 116,208 (1984);
Vyas et al., U.K. Patent Application No. 2,140,799 (1984).
7-Alkoxy substituted mitosanes related structurally to mitomycin A are described as useful antibiotics having activity in experimental animal tumors in an article by Urakawa et al., J. Antibiotics, 23, 804-809 (1980).
Mitomycin C is the principal mitomycin produced by fermentation and is the commercially available form. Current technology for the conversion of mitomycin C to mitomycin A suffers from a number of deficiencies. Hydrolysis of mitomycin C to the corresponding 7-hydroxy-9a-methoxy-mitosane, and then methylation of that substance requires diazomethane, a very hazardous substance to handle on a manufacturing scale, and the 7-hydroxy intermediate is very unstable [Matsui et al., J. Antibiotics, XXI, 189-198 (1968)]. One attempt to avoid these difficulties involves the use of 7-acyloxymitosanes (Kyowa Hakko Kogyo KK Japanese Patent No. J5 6073-085, Farmdoc No. 56227 D/31). Alcoholysis of mitomycin A as described by Urakawa et al , J. Antibiotics, 23, 804-809 (1980) is limited to the production of only specific 7-alkoxy structural types by the availability and reactivity of the alcohol starting materials.